Danish Nationwide Case-control Study Research Articles

Use of statins and risk of myeloproliferative neoplasms: a Danish nationwide case-control study.

Previous studies have indicated a possible cancer-protective effect of statins in solid cancers; however, this has never been investigated in myeloproliferative neoplasms (MPNs). We aimed to investigate the association between statin use and the risk of MPNs in a nested nationwide case-control study, using Danish national population registries. Information on statin use was obtained from the Danish National Prescription Registry, and patients diagnosed with MPNs between 2010 and 2018 were identified from the Danish National Chronic Myeloid Neoplasia Registry. The association between statin use and MPNs was estimated using age- and sex-adjusted odds ratios (ORs) and fully adjusted ORs (aORs), adjusting for prespecified confounders. The study population included 3816 cases with MPNs and 19 080 population controls (5:1) matched for age and sex using incidence density sampling. Overall, 34.9% of the cases and 33.5% of the controls ever used statins, resulting in an OR for MPN of 1.07 (95% confidence interval [CI], 0.99-1.16) and an aOR of 0.87 (95%CI, 0.80-0.96), respectively. 17.2% were categorized as long-term users (≥5 years) among the cases compared with 19.0% among controls, yielding an OR for MPN of 0.90 (95%CI, 0.81-1.00) and an aOR of 0.72 (95%CI, 0.64-0.81). Analysis of the effect of the cumulative duration of statin use revealed a dose-dependent response, and the association was consistent for sex, age, and MPN subgroups and across different statin types. Statin users were associated with significantly lower odds of being diagnosed with an MPN, indicating a possible cancer-preventive effect of statins. The retrospective of this study precludes causal inferences.

Depression related to hormonal contraceptive use as an early indicator of postpartum depression susceptibility: a danish nationwide case-control study

Depression related to hormonal contraceptive use as an early indicator of postpartum depression susceptibility: a danish nationwide case-control study

Autoimmune diseases in microscopic colitis: A Danish nationwide case-control study.

The association between autoimmune diseases and microscopic colitis remains uncertain. To describe the association between autoimmune diseases and microscopic colitis by using a matched case-control design based on nationwide registry data. All adult Danish patients with a diagnosis of microscopic colitis from 2001 to 2018 were identified from nationwide registries. Odds of autoimmune diseases were compared between cases with microscopic colitis and sex- and age-matched controls from the background population in a 1:10 ratio and evaluated by logistic regression calculating odds ratios (OR) with 95% confidence intervals (CI) adjusted for comorbidity. Analyses were stratified according to sex, age and the subtypes of lymphocytic and collagenous colitis. We identified 15597 cases with microscopic colitis and matched to 155910 controls. In total, 3491 (22%) of patients with microscopic colitis had concomitant autoimmune disease compared to 16521 (11%) of controls (OR, 2.46; 95% CI, 2.36-2.56). Adjusting for comorbidities reduced the OR to 2.09 (95% CI, 2.01-2.19). Analyses showed increased ORs with 16 different autoimmune diseases, particularly of gastrointestinal and endocrine origin, and connective tissue disorders. The highest ORs were for coeliac disease (OR=10.15; 95% CI, 8.20-12.6), Crohn's disease (OR=2.47; 95% CI, 2.10-2.91) and ulcerative colitis (OR=6.73; 95% CI, 6.20-7.30). In stratified analyses younger age at diagnosis and collagenous colitis were associated with higher odds. Using nationwide registry data, microscopic colitis was associated with a wide range of autoimmune diseases, especially of gastrointestinal origin. The results suggest an autoimmune predisposition to microscopic colitis.

Depressive symptoms among patients with COPD according to smoking status: a Danish nationwide case-control study of 21 184 patients.

IntroductionDepressive symptoms appear more often among patients with COPD and are associated with reduced disease control and increased mortality. Both smoking and COPD increase the risk of depressive symptoms. Whether smoking cessation among COPD patients affects the occurrence of depressive symptoms is unknown. We hypothesised that smoking cessation in patients with COPD leads to reduced use of antidepressants and fewer admissions to psychiatric hospitals with depression, anxiety or bipolar disorder.MethodsWe conducted a nationwide retrospective case–control study, in patients from The Danish Register for COPD with spirometry-verified COPD, age ≥40 years, a history of smoking and absence of cancer. Consistent smokers were matched 1:1 with ex-smokers using a propensity score model. Prescription fillings of antidepressants and risk of admissions to psychiatric hospitals with either depression, anxiety or bipolar disorder both descriptively was assessed by Cox proportional hazard models.ResultsWe included 21 184 patients. A total of 2011 consistent smokers collected antidepressant prescriptions compared with 1821 ex-smokers. Consistent smoking was associated with increased risk of filling prescription on antidepressants (HR 1.4, 95% CI 1.3–1.5, p<0.0001) and with increased risk of psychiatric hospital admission with either depression, anxiety or bipolar disorder (HR 2.0, 95% CI 1.6–2.5). The associations persisted after adjustment for former use of antidepressants.ConclusionConsistent smoking among COPD patients was associated with increased use of antidepressants and admissions to psychiatric hospitals with either depression, anxiety or bipolar disorder, compared to smoking cessation.

Low-dose aspirin use and risk of head and neck cancer-A Danish nationwide case-control study.

Results concerning a potential preventive effect of aspirin on head and neck cancer (HNC) are conflicting. We examined the association between low-dose aspirin use and HNC risk overall and by degree of human papillomavirus association in a nested case-control study using nationwide registries. Cases (n = 12 389) were all Danish residents diagnosed with primary HNC (2000-2015). Age- and sex-matched population controls (n = 185 835) were selected by risk-set-sampling. Using conditional logistic regression, we estimated multivariable-adjusted odds ratios and 95% confidence intervals for HNC associated with low-dose aspirin use (≥2 prescriptions). No association was observed between low-dose aspirin ever-use and overall HNC (odds ratio: 1.03, 95% confidence interval: 0.97-1.10). Estimates remained neutral according to patterns of use. Low-dose aspirin use appeared to slightly decrease HNC risk among the eldest (71-84 y), independently of human papillomavirus association, while slightly increase HNC risk among younger age groups (30-60, 61-70 y), driven by an increased risk of oral cancer. However, no consistent patterns in risk estimates were found according to duration and consistency of low-dose aspirin use in the age-stratified analyses.

No decrease in fracture risk despite 15 years of treatment evolution for multiple myeloma patients: A Danish nationwide case-control study.

While treatment strategies for multiple myeloma have evolved radically over the last decades, little is known about the risk of fractures for symptomatic multiple myeloma patients over time. To determine the effect of different treatment periods (1996-2000, 2001-2006 and 2007-2011) on the risk of fractures in patients with multiple myeloma. This retrospective case-control study included patients with multiple myeloma in Denmark, using the Danish National Health Service. Cases were defined as patients who had sustained a fracture between 1996 and 2011, and controls were those without a fracture. Exposure was defined as an ICD code for multiple myeloma. Vertebral fractures, gender, and age were considered in secondary analyses. Conditional logistic regression was used to estimate odd ratios (ORs) of fracture risk, and the analyses were adjusted for comorbidities and recent drug use. The study population consisted of 925,341 cases, and the same number of matched controls, of whom 1334 patients with multiple myeloma. Among cases, the risk of any fracture was higher in multiple myeloma patients compared to patients without multiple myeloma (any fracture: ORadj[95% CI] 1996-2000: 1.7[1.3-2.3]; 2001-2006: 1.3[1.1-1.6]; 2007-2011: 1.7[1.4-2.2]). Although fractures were mainly non-vertebral, the risk of vertebral fractures in particular was higher in multiple myeloma patients (vertebral fracture: ORadj[95% CI] 1996-2000: 3.5[1.4-8.6]; 2001-2006: 4.0[1.9-8.2]; 2007-2011: 3.0[1.6-5.7]). Despite new treatment strategies and improved supportive care, this study showed no decreased fracture risk for multiple myeloma patients over time. New treatment strategies, even if they have a positive impact on overall survival, offer no guarantee for a corresponding reduction in bone lesions.

Urinary tract infections and risk of squamous cell carcinoma bladder cancer: A Danish nationwide case-control study.

Schistosoma haematobium infection can lead to squamous cell carcinomas (SCC) of the bladder. Whether this also applies to more common urinary tract infections (UTIs) is unclear. We therefore aimed to investigate the association between UTIs, reflected by the use of specific antibiotics and risk of SCC of the bladder. We conducted a Danish nationwide case-control study and identified histologically verified bladder cancer cases (2000-2015; n = 12,271) and age- and sex-matched cancer-free controls. We computed odds ratios (ORs) with 95% confidence intervals (CI) associating the use of UTI-specific antibiotics with SCC bladder cancer, using conditional logistic regression. We applied a 2-year lag-time to minimize reverse causation. To aid interpretation, similar analyses were performed for other bladder cancer types and other antibiotics. We identified 333 SCC cases (2.7% of all bladder cancers). Compared to no use (0-1 prescription), high-use (≥10 prescriptions) of UTI-specific antibiotics was associated with SCC with an OR of 11.4 (CI 7.6-17.2) and a clear dose-response pattern (ptrend < 0.001). Use of phenoxymethylpenicillin, an antibiotic not used against UTIs, was not associated with SCC after adjustment for use of UTI-specific antibiotics (OR 0.5). Furthermore, UTI-specific antibiotic use was not associated with urothelial carcinomas (n = 11,029; OR 1.13; CI 0.97-1.32). Excluding patients with known urogenital disease did not influence the SCC estimates (overall OR 10.8; CI 6.2-18.9). Data on smoking were lacking, however, a quantitative bias analysis suggested this to be of limited importance. In conclusion, common UTIs are strong, dose-dependent and specifically associated with risk of SCC of the bladder.

No Decrease in Fracture Risk Despite 15 Years of Treatment Evolution in Multiple Myeloma Patients: A Danish Nationwide Case-Control Study

Introduction Bone lesions are one of the primary symptoms in multiple myeloma (MM), and it has been suggested that these lesions adversely impact overall survival (OS). In the last decades, intensified supportive care and new treatment strategies were introduced to improve overall survival and quality of life. Bortezomib may have the capacity to stimulate bone formation, but reduction in skeletal morbidity has not been demonstrated yet. In addition, data on the fracture risk of MM patients in time are lacking. We hypothesized that the improved treatment strategies and supportive care, including the use of bisphosphonates, reduced the risk of fractures in MM patients at the population level. Therefore, the aim of this study is to determine the effect of different treatment periods on the risk of any fracture in patients with MM. Secondary objectives were to determine the risk of vertebral fractures, and the effects of gender and age on the occurrence of all fractures. Methods A case-control study has been performed using data from the Danish National Health Service. Cases were defined as patients who had sustained a fracture between 1996 and 2011, and controls were those without a fracture. To evaluate the risk of fractures in time, we divided this period in three cohorts: 1996-2000, 2001-2006 and 2007-2011. Vertebral fractures, gender, and age were considered in secondary analyses. Conditional logistic regression was used to estimate odds ratios (ORs) of fracture risk, and the analyses were adjusted for comorbidities and recent drug use. Participants Cases (n = 925,341) were defined as patients who had sustained a fracture between 1996 and 2011, and controls (n = 925,341) were those without a fracture. Exposure was defined as an ICD code for MM. Results Among cases, the risk of any fracture was higher in MM patients compared to patients without MM (Table 1, any fracture: ORadj [95% CI] 1996-2000, 1.7 [1.3 to 2.3]; 2001-2006, 1.3 [1.1 to 1.6]; 2007-2011, 1.7 [1.4 to 2.2]). Although fractures were mainly non-vertebral, the risk of vertebral fractures in particular was higher in MM patients (Table 1, vertebral fracture: ORadj [95% CI] 1996-2000, 3.5 [1.4 to 8.6]; 2001-2006, 4.0 [1.9 to 8.2]; 2007-2011, 3.0 [1.6 to 5.7]). The risk of any fracture was just as high for male as for female MM patients in the three different time cohorts (male: ORadj [95% CI] 1996-2000, 1.8 [1.2 to 2.6]; 2001-2006, 1.6 [1.1 to 2.2]; 2007-2011, 1.9 [1.4 to 2.6], and female: ORadj [95% CI] 1996-2000, 1.6 [1.2 to 2.1]; 2001-2006, 1.1 [0.9 to 1.4]; 2007-2011, 1.6 [1.3 to 2.2]), as well as for patients aged ≤65 or &gt;65 years (≤65 years: ORadj [95% CI] 1996-2000, 1.7 [1.04 to 2.6]; 2001-2006, 1.5 [1.03 to 2.2]; 2007-2011, 2.2 [1.5 to 3.2], and &gt;65 years: ORadj [95% CI] 1996-2000, 1.7 [1.3 to 2.2]; 2001-2006, 1.2 [0.96 to 1.5]; 2007-2011, 1.6 [1.3 to 2.1]). Conclusions Despite new treatment strategies and improved supportive care, this nationwide case-control study showed no decreased fracture risk for MM patients over time. It is thus crucial for physicians to be aware of the ever-elevated fracture risk in MM patients, especially of the vertebrae. Further steps are necessary to reduce fracture risk, and at the same time, to improve the OS of these patients. New treatment strategies, even if they have a positive impact on OS, offer no guarantee for a corresponding reduction in bone lesions. Disclosures Bergh: Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: speakers fee; Eli Lilly: Membership on an entity's Board of Directors or advisory committees, Other: speakers fee; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: speakers fee; UCB: Membership on an entity's Board of Directors or advisory committees, Other: speakers fee.

Use of phthalate-containing prescription drugs and the risk of gastric cancer: a Danish nationwide case-control study

Background: Phthalates are used as excipients in some drug products, and up to a 50-fold increased urinary excretion of phthalate metabolites compared to non-users has been demonstrated in users of such products. In vitro studies have demonstrated that phthalates stimulate mechanisms involved in gastric cancer development. We therefore examined the association between cumulative phthalate exposure from drug products and the risk of gastric adenocarcinomas.Methods: Using the Danish Cancer Registry, we identified all patients with incident gastric adenocarcinoma from 2008 to 2015 (n = 1525). Cancer cases were matched to 10 controls. Linking information retrieved from nationwide Danish registries, we determined individual cumulative phthalate exposure to the ortho-phthalates diethyl phthalate (DEP), dibutyl phthalate (DBP) and enteric phthalate polymers from prescription drugs. The association between cumulative phthalate exposure and gastric adenocarcinoma was estimated using conditional logistic regression, adjusting for socioeconomical status and drugs or comorbidities known or suspected to modify the risk of gastric adenocarcinoma.Results: No association was seen for the risk of gastric adenocarcinomas among individuals with high cumulative exposure to ortho-phthalates (exceeding 500 mg) (ORadj 1.22, 95% CI: 0.84–1.77). Likewise, no associations were observed individually for DEP (ORadj 1.06 95% CI: 0.63–1.76) or DBP (ORadj 1.32 95% CI: 0.78–2.23). Cumulative exposure to enteric phthalate polymers exceeding 10,000 mg, did not reveal an association with gastric adenocarcinoma (ORadj 0.79, 95% CI: 0.54–1.16) and no association was seen for individual compounds. Additionally, no dose-response pattern was observed across exposure strata (p = .39, test for trend).Conclusion: We did not find an increased risk of gastric adenocarcinoma among Danish users of phthalate-containing drug products. Our study is limited by a low number of cases exposed to high cumulative doses of phthalates.

Hospital contacts and diagnoses five years prior to HPV vaccination among females referred for suspected adverse vaccine effects: A Danish nationwide case-control study

BackgroundHigh health care utilization before Human Papilloma Virus (HPV) vaccination might be associated with increased risk of suspected adverse effects (AE’s) after vaccination. We investigated the association between hospital contacts and diagnoses before HPV vaccination and risk of later referral to a specialized hospital setting (HPV center) for suspected AE’s. MethodsThe study was a Danish register-based matched case-control study. Cases were females referred to an HPV center. Five controls per case were randomly selected in the source population of HPV vaccinated females. Information on hospital contacts and diagnoses was obtained from the Danish National Patient Registry. Conditional logistic regression analyses were used to investigate the association between having one or more diagnoses in each specific International Classification of Diseases 10th version (ICD-10) chapter five years before the HPV vaccination and subsequent referral to an HPV center. ResultsWe identified 1496 cases and 7480 controls. In total, 80% of the cases versus 65% of the controls had at least one hospital contact prior to HPV vaccination (Prevalence Proportion Ratio - PPR: 1.24 (95% Confidence Interval - CI: 1.21–1.27)), with 24% vs 12% (PPR: 1.97 (95% CI: 1.76–2.19)) having six or more contacts. Cases were more likely to have had a diagnosis in 15 out of 19 ICD-10 chapters before the vaccination, with ORs larger than 1.8 for infectious diseases, psychiatric diseases, diseases of the nervous, circulatory, digestive and musculoskeletal system, unspecific symptoms and unspecific contacts. ConclusionPre-vaccination morbidity and health care utilization seem to play a role in the path leading to suspected AE’s after HPV vaccination. Since many of the diagnoses that were particularly increased before vaccination in referred females are overlapping with the most frequent symptoms reported, we cannot exclude that for some of the females, the suspected AE’s might have been existing already before the vaccination.

Use of antipsychotics and risk of breast cancer: a Danish nationwide case-control study.

Some antipsychotics increase prolactin levels, which might increase the risk of breast cancer. Existing evidence is conflicting and based on sparse data, especially for the increasingly used second-generation antipsychotics. We conducted a nationwide case-control study of the association between antipsychotic use and incident breast cancer. From the Danish Cancer Registry, we identified women with a first-time diagnosis of breast cancer 2000-2015 (n=60 360). For each case, we age-matched 10 female population controls. Using conditional logistic regression, we calculated odds ratios (ORs) for breast cancer associated with use of antipsychotics. We stratified antipsychotics by first- and second-generation status and by ability to induce elevation of prolactin. In total, 4951 cases (8.1%) and 47 643 controls (7.9%) had ever used antipsychotics. Long-term use (≥10 000mg olanzapine equivalents) was associated with breast cancer, with an adjusted OR of 1.18 [95% confidence interval (CI), 1.06, 1.32]. A weak dose-response pattern was seen, with ORs increasing to 1.27 (95% CI 1.01, 1.59) for ≥50 000mg olanzapine equivalents. Associations were similar for first- and second-generation antipsychotics (ORs 1.17 vs. 1.11), but also for nonprolactin inducing-antipsychotics (OR 1.17). Stratifying by oestrogen receptor status, positive associations were seen for oestrogen receptor-positive cancers (long-term use: OR 1.29; 95% CI 1.13, 1.47) while no associations were observed for oestrogen receptor-negative cancers. Overall, our results do not suggest a clinically important association between antipsychotic use and risk of breast cancer. The importance of drug-induced prolactin elevation is unclear but may lead to a slightly increased risk of oestrogen receptor-positive breast cancer.

Statin use and risk for ovarian cancer: a Danish nationwide case–control study

Background:Limited data suggest that statin use reduces the risk for ovarian cancer.Methods:Using Danish nationwide registries, we identified 4103 cases of epithelial ovarian cancer during 2000–2011 and age-matched them to 58 706 risk-set sampled controls. Conditional logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for epithelial ovarian cancer overall, and for histological types, associated with statin use.Results:We observed a neutral association between ever use of statins and epithelial ovarian cancer risk (OR=0.98, 95% CI=0.87–1.10), and no apparent risk variation according to duration, intensity or type of statin use. Decreased ORs associated with statin use were seen for mucinous ovarian cancer (ever statin use: OR=0.63, 95% CI=0.39–1.00).Conclusions:Statin use was not associated with overall risk for epithelial ovarian cancer. The inverse association between statin use and mucinous tumours merits further investigation.

Epstein‐Barr virus‐associated gastric carcinoma among patients with pernicious anemia

Approximately 9% of gastric carcinomas worldwide are associated with Epstein-Barr virus (EBV), making it the most frequent EBV-associated malignancy. Pernicious anemia, a condition with chronic gastritis and achlorhydria, is strongly associated with gastric carcinoma. Both chronic inflammation and the lack of stomach acid may influence the likelihood of EBV infection of the neoplastic gastric epithelium, but the prevalence of EBV-associated gastric carcinoma among patients with pernicious anemia is unknown. Therefore, we conducted a Danish nationwide case-control study comparing gastric carcinoma patients with pernicious anemia (PA-GC) with those without pernicious anemia (nonPA-GC), frequency matched 1:2. Tumor tissues were reclassified by expert histopathologists blinded to pernicious anemia and EBV status. In total, 186 samples (55 PA-GC and 131 nonPA-GC) were identified. EBV-associated gastric carcinoma (EBV-GC) was more common among PA-GC compared with nonPA-GC, adjusted odds ratio (OR) = 2.53 (CI: 0.88; 7.14), p = 0.08, with further adjustment for lymphocytic infiltrate OR = 2.94 (0.99-8.67), p = 0.05. Gastric carcinomas with signet-ring cell morphology were significantly less common in patients with PA-GC compared with nonPA-GC (OR = 0.05, CI 0.01; 0.24). Although these conditions are rare, we found suggestive evidence that EBV-associated gastric carcinomas are more common among gastric carcinoma patients with pernicious anemia compared with those without.

The association between admission for poisoning with paracetamol or other weak analgesics and subsequent admission for psychiatric disorder: a Danish nationwide case–control study

Many cases of paracetamol poisoning are with suicidal intent, but the association between paracetamol poisoning and subsequent psychiatric disorder is unknown. To examine the association between poisoning with paracetamol or other weak analgesics and subsequent psychiatric disorder. The study was set in a nested case-control design and based on nationwide Danish registers. We identified all patients diagnosed with schizophrenia, affective disorder or eating disorder in 1994-1998 and matched population controls. We estimated the relative risk of these psychiatric disorders after admission for paracetamol or nonparacetamol poisoning, adjusting for income, employment and marital status. We included 12,603 cases with psychiatric disorder, and 1.2% had a diagnosis of poisoning compared with 0.2% of the 252,060 matched population controls. Compared with those with no diagnoses of weak analgesic poisoning, the risk of schizophrenia increased 3.9-fold after paracetamol poisoning, and 2.0-fold after nonparacetamol poisoning. The risk of affective disorder increased 12.2-fold after paracetamol poisoning and 2.6-fold after nonparacetamol poisoning. The risk of eating disorder increased 5.0-fold after paracetamol poisoning, and 2.2-fold after nonparacetamol poisoning. The risk of a diagnosis of psychiatric disorder was very high immediately after poisoning and remained increased for more than 10 years. Paracetamol poisoning is a strong risk marker for psychiatric disorder, particularly affective disorders.